Preeclampsia (PE) is a common disorder of pregnancy that complicates 4-7% of all pregnancies. It is a serious condition with acute proteinuria and hypertension and varying degrees of edema after 20 weeks of gestation. PE leads to a severe risk of low birth weight because of prematurity with inherent complications. The pathogenesis is unknown but is assumed to involve placental ischemia.The primary placental disorder results in renal glomerular injury. Established PE is associated with paradoxical suppression of the renin-angiotensin-aldosterone system, RAAS.

Despite suppressed RAAS, patients with PE retain NaCl(sodium chloride) after an intravenous isotonic NaCl overload compared to healthy pregnant women on a low NaCl diet. The investigators believe to have data that provide a possible explanation for the overall relationship between proteinuria, NaCl retension, suppression of RAAS, hypertension and underdevelopment of placenta. Earlier data, which the investigators have confirmed, shows abnormal glomerular loss of the enzyme plasmin/plasminogen from plasma to the urine in PE. Active plasmin in urine from patients with nephrotic syndrome and PE activates the epithelial sodium channel ( ENaC ) in renal collecting duct cells. The investigators hypothesize that loss of plasmin/plasminogen are shared for the diseases with proteinuria, including PE, and that plasmin- driven ENaC (epithelial sodium channel) activation is a causal factor in the pathophysiology of established PE. Hyperactive ENaC causes primary renal sodium retention with secondary suppression of the renin-angiotensin-aldosterone system. Aldosterone is recently established as a placental growth factor.

Plasma-aldosterone levels are significant higher in normal pregnant women. PE is characterized by low aldosterone levels (a discovery the investigators have also confirmed) and by placental underdevelopment.

Excretion of urine proteases (plasmin/plasminogen) in PE leads to an activation of ENaC and hence RAAS is less NaCl sensitive while the blood pressure is more NaCl sensitive compared to healthy pregnant women.

The degree of aldosterone suppression in PE determines placental development

urine Plasmin/plasminogen correlation to the severity of preeclampsia [ Time Frame: 3 years ] [ Designated as safety issue: No ]

We suggest that the loss of plasmin/plasminogen are shared for the diseases with proteinuria, including PE, and that plasmin- driven ENaC activation is a causal factor in the pathophysiology of established PE. We believe that high concentrations of plasmin/plasminogen in the urine correlates to the severity og preeclampsia.

-Another outcome measure is the correlation between plasma aldosterone and the placental (under)development.

Secondary Outcome Measures:

correlation between RAAS components in urine and severity of preeclampsia [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Degree of aldosterone suppression in PE determines placental development [ Time Frame: 3 years ] [ Designated as safety issue: No ]

PE is characterized by low aldosterone levels and by an underdeveloped placenta. In established PE, suppression of aldosterone can possibly contribute to an underdeveloped placenta.

A causal link between the degree of aldosterone suppression and morphological placenta abnormalities is not yet established. We compare blood levels of aldosterone to flow in a. umbilicalis and a.uterine by ultrasound.

Other Outcome Measures:

Correlation between ENaC peptide fragments in urine and severity of preeclampsia [ Time Frame: 3 years ] [ Designated as safety issue: No ]

PE patients with comparable heavy proteinuria have shown that urokinase plasminogen activator (uPA) in the urine has the ability to activate abnormal filtered plasminogen to plasmin. Active plasmin in urine from patients with nephrotic syndrome and PE is able to activate the epithelial sodium channel ( ENaC ) in renal collecting duct cells by proteolytic cleavage - either directly or by the protease prostatin.

patients with preeclampsia are given a diet with a fixed content of sodium chloride ( 50-60 mmol/day ) plus a supplement of sodium chloride tablets ( 150-200 mmol/day) OR they are given placebo tablets.

After 5 days they switch their supplement.

Dietary Supplement: Sodium

supplemental sodium tablets 150-200 mmol/day in 5 days

Dietary Supplement: Placebo

Placebo are given in 5 days

Controls

Controls are given a diet with a fixed content of sodium chloride ( 50-60 mmol/day ) plus a supplement of sodium chloride tablets ( 150-200 mmol/day) OR they are given placebo tablets.

After 5 days they switch their supplement

Dietary Supplement: Sodium

supplemental sodium tablets 150-200 mmol/day in 5 days

Dietary Supplement: Placebo

Placebo are given in 5 days

not-pregnant women

This arm is also a control- group. Controls are given a diet with a fixed content of sodium chloride ( 50-60 mmol/day ) plus a supplement of sodium chloride tablets ( 150-200 mmol/day) OR they are given placebo tablets.

Pregnant with microalbuminuria and proteinuria, but without hypertension (and therefore do not meet the diagnostic criteria for preeclampsia) can also be included. Proteinuria is the most important factor.

It is still possible to test our hypothesis with possible comorbidity such as diabetes, SLE(systemic lupus erythematosus), rheumatoid arthritis and therefore not a reason for exclusion.

Exclusion Criteria:

Hypertension in pregnancy without proteinuria.

Pregestational nephropathy by other unknown reasons.

Early severe preeclampsia.

Organic or systemic disease of clinical relevance, such as malignancy.

Pregnant controls-

Inclusion Criteria:

pregnancy week 28-36

Singleton pregnancy

Uncomplicated pregnancy

Exclusion Criteria:

Hypertension

Any kind of nephropathy

Organic or systemic disease of clinical relevance, such as malignancy.

Non-pregnant controls:

Inclusion Criteria:

woman, not pregnant

Matched by age and BMI

Exclusion Criteria:

Hypertension

Any kind of nephropathy

Organic or systemic disease of clinical relevance, such as malignancy.

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01828138

Locations

Denmark

Gynelogical Obstetrical Department

Skejby, Aarhus, Denmark, 8200

Sponsors and Collaborators

Odense University Hospital

The Danish Council for Strategic Research

Lundbeck Foundation

Investigators

Study Director:

Boye L. Jensen, Professor

cardiovascular and renal research department, Odense University Hospital